ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2013
Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review.BioMed research international · 2016Pooled it
- C781, a β-Arrestin Biased Antagonist at Protease-Activated Receptor-2 (PAR2), Displays in vivo Efficacy Against Protease-Induced Pain in Mice.The journal of pain · 2023Article
- β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation.British journal of pharmacology · 2023Article
- Alternaria alternata-induced airway epithelial signaling and inflammatory responses via protease-activated receptor-2 expression.Biochemical and biophysical research communications · 2022Article
- Myeloid-associated differentiation marker is a novel SP-A-associated transmembrane protein whose expression on airway epithelial cells correlates with asthma severity.Scientific reports · 2021Article
- A Role for Protease Activated Receptor Type 3 (PAR3) in Nociception Demonstrated Through Development of a Novel Peptide Agonist.The journal of pain · 2021Article
- Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2.RSC medicinal chemistry · 2020Article
- Genetic Variation in Surfactant Protein-A2 Delays Resolution of Eosinophilia in Asthma.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Lipidated connexin mimetic peptides potently inhibit gap junction-mediated CaAmerican journal of physiology. Cell physiology · 2018Article
- Protease-activated receptors in kidney disease progression.American journal of physiology. Renal physiology · 2016Review
- Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones.Pharmacology & therapeutics · 2016Review
- Imaging of targeted lipid microbubbles to detect cancer cells using third harmonic generation microscopy.Biomedical optics express · 2016Article
- Airway epithelial cell exposure to distinct e-cigarette liquid flavorings reveals toxicity thresholds and activation of CFTR by the chocolate flavoring 2,5-dimethypyrazine.Respiratory research · 2016Article
- Potent Small Agonists of Protease Activated Receptor 2.ACS medicinal chemistry letters · 2016Article
- The novel PAR2 ligand C391 blocks multiple PAR2 signalling pathways in vitro and in vivo.British journal of pharmacology · 2015Article
- Article
- A highly potent agonist to protease-activated receptor-2 reveals apical activation of the airway epithelium resulting in Ca2+-regulated ion conductance.American journal of physiology. Cell physiology · 2014Article
- Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma.Current opinion in pharmacology · 2014Review
- Development and evaluation of small peptidomimetic ligands to protease-activated receptor-2 (PAR2) through the use of lipid tethering.PloS one · 2014Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Protease-activated receptor-2 (PAR₂) is a G-protein coupled receptor (GPCR) associated with a variety of pathologies. However, the therapeutic potential of PAR₂ is limited by a lack of potent and specific ligands. Following proteolytic cleavage, PAR₂ is activated through a tethered ligand. Hence, we reasoned that lipidation of peptidomimetic ligands could promote membrane targeting and thus significantly improve potency and constructed a series of synthetic tethered ligands (STLs). STLs contained a peptidomimetic PAR₂ agonist (2-aminothiazol-4-yl-LIGRL-NH₂) bound to a palmitoyl group (Pam) via polyethylene glycol (PEG) linkers. In a high-throughput physiological assay, these STL agonists displayed EC₅₀ values as low as 1.47 nM, representing a ∼200 fold improvement over the untethered parent ligand. Similarly, these STL agonists were potent activators of signaling pathways associated with PAR₂: EC₅₀ for Ca(2+) response as low as 3.95 nM; EC₅₀ for MAPK response as low as 9.49 nM. Moreover, STLs demonstrated significant improvement in potency in vivo, evoking mechanical allodynia with an EC₅₀ of 14.4 pmol. STLs failed to elicit responses in PAR2(-/-) cells at agonist concentrations of >300-fold their EC₅₀ values. Our results demonstrate that the STL approach is a powerful tool for increasing ligand potency at PAR₂ and represent opportunities for drug development at other protease activated receptors and across GPCRs.
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